Drug Evaluation
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Teriflunomide: a novel oral treatment for relapsing multiple sclerosis 1.
Introduction
2.
Pharmacodynamics
3.
Pharmacokinetics and
Arianna Sartori†, Dawn Carle & Mark S Freedman †
University of Trieste, Ospedale di Cattinara - Azienda Ospedaliero-Universitaria Ospedali Riuniti, Department of Medical, Surgical and Health Sciences (Neurology), Trieste, Italy
metabolism 4.
Clinical trials
5.
Safety and tolerability
6.
Regulatory affairs
7.
Conclusion
8.
Expert opinion
Introduction: Multiple sclerosis is a disabling chronic inflammatory disease of the CNS. New emerging oral treatments can offer efficacy with higher levels of therapeutic adherence. Teriflunomide is one such oral agent that has recently been approved for the treatment of relapsing multiple sclerosis (RMS). Areas covered: The aim of this review is to describe the pharmacological profile of teriflunomide and review the vast clinical development program that paved the way for its approval, with emphasis on its safety and tolerability. Expert opinion: Teriflunomide is a safe new oral medication for treating RMS. It is effective at reducing relapses, MRI activity and slowing disability progression. It is well tolerated, with mild and transitory side effects. Although teriflunomide is given a pregnancy category ‘X’ by the FDA and an effective contraception is needed, to date, there has been no evidence of teratogenicity in humans and a rapid washout procedure can lead to a virtually complete elimination. Its effectiveness appeared to be at least comparable to that of high-dose IFN-b-1a, and although direct comparisons with other orals are still lacking, its tolerability and encouraging safety data suggest that teriflunomide could be considered an ideal first-line medication for RMS. Keywords: disease-modifying therapy, oral agent, relapsing multiple sclerosis, teriflunomide Expert Opin. Pharmacother. (2014) 15(7):1019-1027
1.
Introduction
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS that causes demyelination and axonal loss; it represents one of the most important causes of disability in young adults. Only 20% of patients experience a progressive form at onset (primary progressive MS), whereas the majority of patients present with a relapsing-remitting course that can eventually turn into secondary progressive disease [1]. Several medications are currently available to reduce the number of relapses, reduce MRI activity and delay progression of disease, but few have ever been definitively shown to prevent the transition to the secondary progressive phase. Moreover, they are often associated with side effects that can reduce tolerability. Overview of the market The first available disease-modifying drugs (DMD) for relapsing MS (RMS) were injectable and included IFN-b-1a, IFN-b-1b and glatiramer acetate (GA). Despite an excellent long-term safety profile, injection site reactions, flu-like syndromes and the injection itself still represent an obstacle to the achievement of the highest levels of adherence. Oral therapies could therefore fulfill the unmet need for a more tolerable therapy, leading to improved adherence and, as a result, effectiveness. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator [2], was the first oral drug to receive North American and European regulatory approval, but there 1.1
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Teriflunomide Currently III -- IV RMS DHODH inhibitor and subsequent inhibition of de novo pyrimidine synthesis Route of administration Oral Chemical structure C12H9F3N2O2 Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/19/14 For personal use only.
Drug name Phase Indication Pharmacology
CH3
N
2. OH
O
NH
F
F F
Pivotal trial(s)
TEMSO, TOWER, TENERE, TOPIC
DHODH: Dihydroorotate dehydrogenase; RMS: Relapsing multiple sclerosis.
is still some hesitation in the regular use of this drug, related at least partially to a concern regarding cardiovascular adverse events. Promising next-generation selective sphingosine receptor modulators, such as siponimod [3], ponesimod [4] and ceralifimod [5], are currently under study, with the hope of providing similar efficacy but with a better safety profile. Dimethyl fumarate (DMF), a fumaric acid ester, has been recently approved in many countries, including Canada and the USA as a treatment for RMS [6]. This agent is the main component of a combination of fumaric acid esters (Fumaderm) used in Germany for the treatment of psoriasis. The mechanism of action is not completely understood: it exerts a positive anti-inflammatory effect by mainly acting upon a transcription factor (the nuclear factor erythroid 2-related factor 2 (Nrf-2)). The medication ultimately can be well tolerated despite early side effects of flushing and gastrointestinal (GI) disturbances (diarrhea, nausea, abdominal pain), which diminish after the first months. A recent report of some cases of progressive multifocal leukoencephalopathy (PML) in patients with psoriasis treated with Fumaderm is raising some safety concerns with DMF treatment in MS [7,8]. Laquinimod is another oral drug with an unknown mechanism of action, which showed some early promise in clinical trials in that despite a relatively modest effect on relapse and MRI activity reduction, it appeared to have a statistically significant effect at slowing expanded disability status scale (EDSS) progression, as well as reducing brain atrophy compared with placebo [9]. 1020
Introduction to the compound and chemistry Teriflunomide is a once-daily oral medication approved in many countries for the treatment of RMS (Box 1). It is the most important active metabolite of leflunomide, a synthetic low-molecular-weight isoxazole derivative, previously used for the treatment of active rheumatoid arthritis for the past 15 years. 1.2
Box 1. Drug summary.
Pharmacodynamics
Teriflunomide acts as a noncompetitive and reversible inhibitor of the dihydroorotate dehydrogenase (DHODH), the fourth mitochondrial enzyme of de novo pyrimidine synthesis [10]. As a consequence, it inhibits the proliferation of highly dividing cell pools and in particular, T- and B-activated autoreactive cells, thought to be responsible for the inflammation and damage observed in MS. The pyrimidine salvage pathway is spared, and this allows maintenance of a protective immunity despite treatment. Teriflunomide is effectively a cytostatic drug, not cytotoxic, as it does not affect lymphocyte viability. In an in vitro study on stimulated peripheral blood mononuclear cells (PBMCs), teriflunomide showed a significant dose-dependent and reversible inhibition of T- and B-cell proliferation but only a little to no impact on their activation [11]. Further evidence supporting this observation comes from the pooled analysis of the safety data from three placebo-controlled teriflunomide studies (involving > 2500 patient-years of teriflunomide exposure) showing that the maximum mean decreases in neutrophil and lymphocyte counts were ~ 15%, but the mean absolute counts were within normal range and there was no association with increased number of infections [12]. Teriflunomide-treated patients maintain their ability to mount effective immune responses to seasonal influenza vaccination [13]; they also mount lower but effective antibody response and substantially equal cellular responses to Rabies vaccine as compared with placebo [14]. Finally, it has been very elegantly demonstrated in vitro that the suppressive effect of teriflunomide on T cells might depend on the quality of T-cell activation: it does not act as a nonselective suppressor of T-cell proliferation and expansion, but it blocks only the high-affinity T-cell clones’ expansion, although the low affinity T-cell clones are free to exert the immune response. In particular, it exerts a strong action only upon high-affinity T-cell receptor (TCR) stimulation and with high antigen concentrations although the effects upon low affinity TCR are modest. This translates into a selective immune modulation rather than a nonselective suppression of T-cell proliferation/ expansion as previously thought [15]. Many other DHODH-independent functions of teriflunomide have been invoked, but their relevance in vivo is still questioned. Indeed, in vitro models have shown its capacity to inhibit tyrosine kinases, MAPKs, nuclear factor k-lightchain-enhancer of activated B cells and cyclooxygenase-2;
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Teriflunomide
however, the concentrations used in these models are at least an order of magnitude higher than the concentrations needed to exert its effect on DHODH [16]. Teriflunomide also prevented stimulated PBMCs to express or release proinflammatory cytokines such as IL-6, IL-8 and monocyte chemotactic protein-1 with a DHODH-independent mechanism [11]. Teriflunomide was also shown to be efficacious in a number of animal models. In the Dark Agouti (DA) rat model of experimental autoimmune encephalomyelitis (EAE), which can more closely mimic the relapsing remitting course MS, teriflunomide reduced inflammation, axonal damage and functional deficits both in a prophylactic and therapeutic setting, and in a dose-dependent manner [17]. Moreover, teriflunomide prevented the EAE-increased latencies in somatosensory-evoked potentials and, as more recently demonstrated, in motor-evoked potentials [18]. Teriflunomide treatment attenuated the number of spinal cord-infiltrating T cells, natural killer cells, macrophages and neutrophils in DA rats with EAE, and it tended to normalize peripheral immune cell changes induced by the disease [19]. Teriflunomide has also been shown to decrease CSF levels of the chemokines CXCL9 and CXCL10 in Theiler’s encephalomyelitis virus-induced demyelinating disease model of MS, induced in SJL mice [20]. 3.
Pharmacokinetics and metabolism
The median half-life (t1/2) of the compound is 18 -- 19 days after repeated oral doses of 7 and 14 mg and it takes 3 months to reach the steady-state concentrations. It is > 99% plasma protein bound, therefore it has an approximately 100% bioavailability and a distribution volume of 11 l [21]. Teriflunomide metabolism is hepatic and requires hydrolysis, oxidation, N-acetylation and sulfate conjugation, with minimal burden for cytochrome P450. The unchanged drug undergoes direct biliary excretion, while the kidney excretes the majority of its metabolites. The enterohepatic recycling process allows teriflunomide to be reabsorbed in the small intestine and to be carried again in the liver through the portal circulation [22]. Therefore, it has very slow plasma elimination and it takes from 8 to 24 months to reach levels below 0.02 µg/ml. Nevertheless, if needed (e.g., unexpected serious adverse event (SAE) or pregnancy), it can be easily eliminated with an accelerated procedure that forms insoluble complexes bound in the small intestine, leading to a > 98% of decrease in plasma teriflunomide concentrations. For this purpose, either cholestyramine (8 g three times daily for 11 days) or activated charcoal (50 g activated charcoal twice daily for 11 days) can be used [23]. 4.
Clinical trials
Phase II studies The Phase II study [ClinicalTrials.gov identifier: NCT01487096] [24] aimed to examine the safety, efficacy 4.1
and optimal oral administration dose of the drug in patients with RMS. It was a randomized, double-blind, placebocontrolled, parallel-group trial with an MRI metric primary end point (number of combined unique [CU] active lesions). The study involved 179 patients who were randomized (1:1:1) and treated with placebo (n = 61), teriflunomide 7 mg/day (n = 61), or teriflunomide 14 mg/day (n = 57) for 36 weeks. There was a significant reduction in the median CU number in both treatment groups (teriflunomide 7 mg = 0.2, p < 0.03; teriflunomide 14 mg = 0.3, p < 0.01) compared with placebo (0.5), as well as a lower number of gadolinium (Gd)-enhanced lesions and of new or enlarging T2 lesions. There was a trend towards the reduction of the annualized relapse rates (ARRs) versus placebo-treated patients (mean ± SD = 0.58 ± 0.85 and 0.55 ± 1.12 vs 0.81 ± 1.22; p = NS). Despite these modest relapse results, it was of interest that teriflunomide 14 mg/day group showed a lower increase of disability (EDSS score) compared with the placebo group (7.4 vs 21.3%; p = 0.04). 4.2
Phase III studies TEMSO
4.2.1
The TEriflunomide Multiple Sclerosis Oral trial (TEMSO; ClinicalTrials.gov identifier: NCT00134563) was the first teriflunomide Phase III study; a double-blind, placebocontrolled study that enrolled 1088 patients with RMS, randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg, or 14 mg of teriflunomide once daily for 108 weeks [25]. Inclusion criteria were 18 -- 55 years of age, RMS according to the McDonald criteria [26] (with or without progression), an EDSS score £ 5.5, ‡ 2 clinical relapses in the previous 2 years (or one in the previous), and no attacks in the 60 days before randomization. The demographic and clinical characteristics at baseline were well balanced between three groups. The primary end point was met as teriflunomide significantly reduced the adjusted ARRs (95% CI) (0.54 for placebo vs 0.37 for teriflunomide at either 7 or 14 mg; p < 0.001 for both comparisons), as well as the secondary end point, consisting of the reduction in sustained disability progression, although no significant result was observed in the 7 mg group. Also, MRI end points were met: significantly lower total lesion volume (key MRI endpoint), fewer Gd-enhancing lesions and unique active lesions were observed in both teriflunomide groups compared with placebo [27]. Changes on brain atrophy and effect on fatigue did not differ significantly among the three groups. A prespecified subgroup analysis showed a constant and significant superiority of both treatment groups across all subgroups (stratification according to age, gender, geographical region, clinical disease characteristics, relapses in the past 2 years, MS subtype, MRI basal features, previous use of DMDs) [28]. Also, sustained disease-free activity was considered in the post hoc analysis, underlying a significant advantage for both treatment groups compared with placebo (disease-free patients were 14.3% in the placebo group, 18.4% in the 7 mg teriflunomide group and 22.9% in
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the 14 mg teriflunomide group [p = 0.0293 and p = 0.0002 vs placebo, respectively]) [29]. Finally, both teriflunomide 7 and 14 mg treatment reduced the annualized rates of relapses with sequelae, the relapses leading to hospitalization or requiring i.v. corticosteroids, and teriflunomide 14 mg also decreased annualized rates of all hospitalizations [30]. In the TEMSO extension study (ClinicalTrials.gov identifier: NCT00803049), patients who previously received placebo were re-randomized 1:1 to teriflunomide 7 or 14 mg. The 8-year follow-up (cutoff June 2012) confirmed low relapse rates, with an unchanged safety profile [31]. TOWER The second Phase III clinical trial (Teriflunomide Oral in People with Relapsing-Remitting Multiple Sclerosis [TOWER]; ClinicalTrials.gov identifier: NCT00751881) enrolled 1096 patients with the same inclusion criteria; the duration of the study was variable according to the timing of enrollment as it ended when the last patient included completed 48 weeks of treatment. The results confirmed what TEMSO study already stated: there was a significant reduction of the annual relapse rate (ARR) in both teriflunomide groups compared with placebo (teriflunomide 7 mg reduced ARR by 22.3%; p = 0.018; teriflunomide 14 mg reduced 36.3%; p < 0.001). The effect on the disability progression was significant only for the highest dosage (31.5%, p = 0.044) [32]. Similarly, in the TOWER post hoc analyses, it was clear that teriflunomide significantly reduced the number of relapses with sequelae and need of corticosteroid treatment [33]. Overall, ARR was reduced by 33.7 and 27% with teriflunomide 14 and 7 mg, respectively (p < 0.0001 vs placebo in both dosages). Disability progression was reduced by 30.5% (p = 0.0029) with only the higher 14 mg dosage, while teriflunomide 7 mg effect did not reach the statistical significance, as shown in the pooled efficacy data from TEMSO and TOWER [34]. Similarly, teriflunomide reduced also relapses with sequelae, relapses leading to hospitalization, those requiring corticosteroids, and teriflunomide 14 mg also reduced severe relapses (defined by Panitch) [35,36].
or IFN-b-1a on the primary composite end point (time to failure, defined as the first occurrence of confirmed relapse or permanent treatment discontinuation for any cause). Although teriflunomide was not found to be superior, it appeared to have an effect on ARR that was not significantly different than IFN-b-1a (IFN-b-1a = 0.22 vs teriflunomide 14 mg = 0.26, p = 0.6), whereas teriflunomide 7 mg showed paradoxically a significantly higher ARR compared with IFN-b-1a. The changes in the Fatigue Impact Scale favored teriflunomide as well as the mean scores in the Treatment Satisfaction Questionnaire for Medication (version 1.4), evaluating fatigue and treatment satisfaction, respectively [37].
4.2.2
TENERE TENERE (TErifluNomidE and REbif; ClinicalTrials.gov identifier: NCT00883337) was the first Phase III, raterblinded study, in which teriflunomide was compared with IFN-b-1a to evaluate its effectiveness, safety and tolerability in patients with RMS. The inclusion criteria remained the same as the other studies, but patients with history of prior use of subcutaneous IFN-b-1a, teriflunomide, leflunomide, prior or ongoing use of natalizumab, cladribine, mitoxantrone, or other immunosuppressants, or use of other IFNs, GA, intravenous immunoglobulins, or cytokine therapy within 3 months were excluded. A total of 324 patients were randomized 1:1:1 to teriflunomide 7 or 14 mg (double-blind) or subcutaneous IFN-b-1a 44 mcg t.i.w. (open-label). The study failed to show any difference between either dose of teriflunomide 4.2.3
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TOPIC The effectiveness of teriflunomide in patients with clinically isolated syndrome (CIS) was assessed in the TOPIC study (ClinicalTrials.gov identifier: NCT00622700), a doubleblind, placebo-controlled, parallel-group study. A total of 618 CIS patients were randomized to placebo, teriflunomide 7 or 14 mg. The slow recruitment due to the availability of other medications for CIS treatment together with the introduction of the newer 2010 diagnostic criteria [38], which rendered obsolete the primary end point, led to the premature interruption of this study. Collected data have been evaluated and both the primary and the key secondary end points were met: there was a reduction of the risk to convert to clinically definite MS (CDMS) by 42.6% (p = 0.0087) and 37.2% (p = 0.0271) in the 14 and 7 mg groups, respectively, compared with placebo. Moreover, a significant reduction of the risk of occurrence of new relapse or new MRI lesion was observed in both active treatment groups [39]. 4.2.4
Adjunctive therapy studies Teriflunomide has been purposed also in association with other immunomodulatory therapies with different mechanisms of action. It was administrated as adjunctive treatment to ongoing GA for 6 months, with a 6-month extension (ClinicalTrials.gov identifier: NCT00489489) [40]. A total of 123 RMS patients were randomized (1:1:1) to placebo, teriflunomide 7 mg and teriflunomide 14 mg, and the association with 7 mg teriflunomide demonstrated a significant reduction in the number of T1-Gd lesions and relative risk reductions of 64% (p = 0.031) and 47% (p = 0.193) with 7 and 14 mg, respectively. These results probably reflected the higher baseline MRI disease activity in the 7 mg group. Another Phase II trial randomized 118 patients on stable dose of IFN-b therapy to placebo, teriflunomide 7 mg, or teriflunomide 14 mg adjunctive therapy (1:1:1) [41], and the respective adjusted ARRs were 0.343, 0.231 and 0.144 (relative decrease in ARR of 32.6% [p = 0.4355] and 57.9% [p = 0.1005] in 7 and 14 mg groups, respectively, vs placebo). A significantly unexpected reduction in the number of T1-Gd lesions in both teriflunomide dosage groups was observed, which was greater than was seen with either IFN-b or teriflunomide alone, suggesting an additive or synergistic effect of the combination. 4.3
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Teriflunomide
These encouraging results led to TERACLES, a Phase III study (ClinicalTrials.gov identifier: NCT01252355) testing the efficacy and tolerability of teriflunomide in combination with IFN-b [42]. The study has been prematurely interrupted, and the data analysis is ongoing. 5.
Safety and tolerability
5.1
Overview of TEAEs and SAEs
between the groups in the incidence of ALT > 3 upper limit of normal (ULN) and serious hepatic disorders [12]. None of the ALT elevations were associated with concomitant elevations in bilirubin. All the trial protocols required treatment discontinuation should ALT > 3 ULN occur on two consecutive laboratory measurements. Infections The occurrence of serious infections was rare (£ 2.5%) and similar in all groups, with an approximately 15% maximum mean decreases in neutrophil and lymphocyte counts (mean absolute counts within the normal range, no increased infection rate) [12].
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5.1.2
The safety profile was recently updated, pooling the data from the three double-blind studies, and both doses seemed to have a similar and manageable safety profile [12]. The analysis from 2430 patients (cumulative treatment exposure > 1225 patientyears per group) revealed that the treatment-emergent adverse events (TEAEs) more frequently reported were hair thinning, diarrhea, alanine aminotransferase (ALT) elevation, nausea and headache. Treatment discontinuations in the teriflunomide group were due to TEAEs (placebo 6.9%; teriflunomide 7 mg 11.0%; teriflunomide 14 mg 13.6%), but many of these were related to protocol requirements (repeated ALT elevations). The extension studies, with up to 9 years’ exposure to teriflunomide, showed no unexpected TEAEs. In particular, in the Phase II extension trial (ClinicalTrials. gov identifier: NCT00228163) [43], involving 147 patients from the core study, there were 15 (18.5%) and 13 (19.7%) patients in the 7 and 14 mg groups, respectively, who discontinued because of the occurrence of TEAEs. SAEs were reported in 29 (35.8%) and 19 (28.8%) patients in the 7 and 14 mg groups, respectively. They were increased hepatic enzymes (n = 10), increased ALT (n = 3), loss of consciousness (n = 3), pneumonia (n = 2), neutropenia (n = 2), breast cancer (n = 2) and MS relapse (n = 2). SAEs that led to discontinuation were described in 11 (13.6%) and 9 (13.6%) patients. The TEMSO extension trial [31] included patients treated for up to 8 years (cutoff June 2012). The most common TEAEs, whose incidence did not change between groups or increased with treatment duration, were nasopharyngitis, diarrhea, hair thinning, increased ALT, influenza, pain in extremity and headache. SAEs occurred in 20% of patients: increased ALT (n = 14), intervertebral disc protrusion (n = 7), venous stenosis (n = 4), urinary tract infection (n = 4) and pneumonia (n = 3). Overall, seven deaths occurred and none of them have been considered related to the treatment. One and three deaths were seen during the Phase II and the TEMSO study extensions, respectively, and three during the TOWER study (due to motor vehicle accident, suicide, sepsis) [32]. The TENERE study reaffirmed the same safety profile, with a lower discontinuation rate due to AEs in the teriflunomide group compared with the IFN-b-1a group [37]. The number of serious TEAEs and TEAEs leading to treatment discontinuation was low also in the adjunctive therapy studies [40,41]. Hepatic effects Teriflunomide treatment most often caused asymptomatic and transient ALT elevations, but there was no difference 5.1.1
Malignancies In the three placebo-controlled studies, neoplasms (benign or malignant) were very rarely observed (< 0.5% of patients; placebo n = 4; teriflunomide 7 mg n = 1; teriflunomide 14 mg n = 3), without a specific pattern of occurrence. No hematooncological cancers were reported. These data were confirmed by the extension studies, in which the prevalence of malignancies reflected the rates observed in the general population. 5.1.3
Blood pressure At week 108, a slight elevation in diastolic and more marked in systolic blood pressure was observed in the teriflunomide group compared with placebo (systolic: placebo -0.7, teriflunomide 7 mg +3.0, teriflunomide 14 mg +2.7; diastolic: placebo -0.7, teriflunomide 7 mg +1.4, teriflunomide 14 mg +1.6) [12]. In spite of the slight blood pressure elevation in the teriflunomide group, none of the cases was severe or led to therapy discontinuation. 5.1.4
GI symptoms The most frequently reported TEAEs are diarrhea and nausea, which are usually of mild or moderate intensity, and their incidence is higher during the first 3 months of treatment, which then tends to decrease. They usually resolve spontaneously [44]. 5.1.5
Hair loss/hair thinning The analysis of the data from the Phase II and TEMSO studies showed that hair thinning/loss was more common in the teriflunomide group, with a trend towards a dose--effect (placebo 4.3%, teriflunomide 7 mg 11.4% and teriflunomide 14 mg 15.2%). Less than one per cent of patients discontinued treatment because of that TEAE and usually it was graded as mild (73%) or moderate in intensity. The type of hair thinning/loss was telogen effluvium, characterized by acceleration toward the resting phase of the follicular growth cycle. This is a reversible phenomenon, which in the majority of the patients resolved spontaneously within 3 -- 6 months, without sequelae (85%) and while patients were still on treatment [45]. 5.1.6
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5.1.7
Peripheral neuropathy
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In the TEMSO study, 10 confirmed cases of peripheral neuropathies were observed (1.2% of the teriflunomide 7 mg group and 1.9% of the teriflunomide 14 mg group); no cases in the placebo group were reported. In particular, there were five mononeuropathies related to carpal tunnel syndrome or nerve compression, and three resolved spontaneously during treatment [25]. Pregnancy The teratogenic potential of leflunomide, suggested by animal models, led to the required reliable contraception during clinical trials as well as during the postmarketing use. In spite of that, a total of 81 pregnancies were reported in female patients and 20 in partners of male patients (clinical trial database, data cutoff 9 April 2013). One study, with eight pregnancies, remains blinded. The available outcomes from 63 pregnancies in women exposed are as follows: 20 healthy newborns, 26 induced abortions, 12 spontaneous abortions and 5 ongoing pregnancies. Pregnancy outcomes from 16 in partners of men exposed to the drug are 12 healthy newborns, 1 induced abortion, 1 spontaneous abortion and 2 ongoing pregnancies. No structural defects or functional deficits were noticed in newborns. The 19% spontaneous abortion rate reflects the rates in similar MS patients [46]. Even though the safety data are encouraging, patients should use reliable contraception while on teriflunomide as well as discontinue treatment and undergo accelerated elimination (with cholestyramine or activated charcoal) prior to conceiving. Recently presented experimental data from in vitro and in vivo (animal model) studies showed that teriflunomide has no effects on sperm DNA [47]. 5.1.8
6.
Regulatory affairs
Teriflunomide has been approved for the treatment of RMS by the US FDA in September 2012 (7 and 14 mg dosages) and by the European Medicines Agency in August 2013 (only 14 mg dosage) and in November 2013 also in Canada and Australia. 7.
Conclusion
Teriflunomide is a recently approved oral DMD for RMS, with a once-daily dosing. Its properties affecting the pool of nucleotides used by rapidly dividing cells but not changing cell DNA structure ultimately leading to fewer autoimmune T cell make it more like an immunomodulator rather than an immunosuppressant. Phase II and III studies showed reduction in ARRs, MRI activity and disability progression in treated patients. In the head-to-head study, teriflunomide was not superior to IFN-b-1a, but produced relapse rate reductions not significantly different from the high-dose IFN-b-1a, although comparisons with other DMDs are still lacking. In the CIS population, it reduced the risk to convert 1024
to CDMS. It has an excellent safety profile, confirmed also in the adjunctive therapy studies. 8.
Expert opinion
Teriflunomide most clearly showed its effects on the primary outcome measure of ARR reduction, though the 14 mg dose also repeatedly showed significant slowing of EDSS progression and a reduction in most important secondary MRI end points -- findings that were consistent across the different patient subgroups analyzed in both TEMSO and TOWER trials [28,32]. It did not have a significant effect on slowing brain atrophy relative to placebo over 2 years in TEMSO. Nevertheless, it is a simple, safe and well-tolerated oncedaily oral treatment, which is thus seen as an advantage over any of the current self-injectable therapies. Its main disadvantage over the injectables is the lack of long-term nontrial safety data. The injectables have proven to be extremely safe as they have been used for almost 30 years without significant concerns, but teriflunomide has a 12-year history of extremely encouraging clinical trial data to add to a much longer history of its parent drug leflunomide in the treatment of rheumatoid arthritis. Teriflunomide produced thus far no unexpected severe adverse events or deaths in any study. It was very well tolerated, and the main side effects reported were mild and transitory. In particular, GI side effects usually resolved in the first 3 months and they led to discontinuation of study therapy in only a small percentage of patients (teriflunomide 7 mg = 1.4%, teriflunomide 14 mg = 1.1%, placebo = 0.3%) [44]. Also, hair loss/thinning was transitory and usually resolved spontaneously while still on treatment without sequelae, which distinguishes this type of hair loss from that seen frequently with the use of chemotherapy. As with GI side effects, discontinuations due to hair loss occurred only in a very few cases (teriflunomide 7 mg = 0.5%, teriflunomide 14 mg = 1.4%, placebo = 0%) [45]. Finally, one of the main concerns is the potential teratogenic action of teriflunomide, which was based on the noted effect of its parent drug leflunomide in animal models leading to the FDA ‘X’ rating for safety in pregnancy. Regardless, pregnancies did occur during the clinical trial program of teriflunomide and an ongoing registry continues to collect postmarketing information, and thus far there is no clear evidence of teratogenicity in humans [46]. By no means does this suggest it is safe to take during pregnancy and effective contraception remains fundamental as it does for the other available MS treatments. Some feel that this potential for teratogenicity, however not realized in > 15 years of combined monitoring of leflunomide [48,49] and teriflunomide, warrants it being relatively contraindicated for young fertile women. However, we take the opposite view as teriflunomide is the only diseasemodifying medication for which there is a highly effective and simple procedure for its complete elimination from the body that takes < 2 weeks. Thus, a young woman wishing to become pregnant needs only to perform the ‘washout’
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Teriflunomide
procedure using cholestyramine or charcoal, then gets a free serum teriflunomide blood test showing levels of teriflunomide below that of teratogenic potential, and she would be safe to conceive immediately. The safety of all other therapies is not established, but neither is the time it takes to wash out the other treatments from the body. Most physicians arbitrarily recommend waiting 2 -- 3 months following the cessation of an MS treatment before trying to conceive. Direct comparisons to other oral therapies are still lacking. In the CONFIRM [50] study, although not statistically powered for a comparison between DMF and GA, the drugs did not appear to differ in terms of ARR reduction. In the TRANSFORMS study [51], Fingolimod demonstrated its superiority to low-dose once-weekly IFN-b-1a IM in reducing ARR and MRI activity. Although we do know that teriflunomide effectiveness is at least comparable to high-dose IFN-b-1a, which has been shown to be more efficacious than once-weekly IFN-b-1a IM [36,52], in the TENERE study it was not more effective than high-dose IFN-b-1a SC in terms of relapse reduction or treatment discontinuations. Once physicians realize the simplicity and safety of teriflunomide, it should be readily embraced as a first-line alternative therapy to the injectables. Its tolerance profile and once-daily regimen are advantages over DMF, offering somewhat comparable efficacy in most countries for a cheaper price. Moreover, recently the Canadian Drug Expert Committee recommended, based on a cost-effectiveness analysis, that DMF should be used for the treatment of RRMS only Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502-17
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Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsingremitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol 2013;12:756-67 Freedman MS, Boster A, Fernandez O, et al. Long-term efficacy, safety and tolerability of ponesimod in patients with relapsing--remitting multiple sclerosis. Neurology 2013;80:P01.156 Vollmer T, Selmaj K, Bar-Or A, et al. A double-blind, placebo-controlled, Phase 2, 26-week DreaMS trial of a selective S1P receptor agonist ONO4641 in patients with relapsing-remitting
if the patient has failed to respond to adequate courses of at least one IFN-b formulation and GA [53]. Until properly conducted comparator trials are performed, which are unlikely, it will be difficult to know how any of the oral agents do relative to each other let alone the incumbent therapies. Longer-term ‘real-world’ safety data might well indicate which agent may be more risky; already there are concerns that DMF, at least in the treatment of psoriasis, might be a risk for the development of PML [7,8]. We envisage teriflunomide to take a foothold of first-line therapies for MS around the world, having the most extensively studied oral agent in CIS and in three Phase III trials in RMS and now planning to be studied in the pediatric population.
Declaration of interest MS Freedman has received research grants from Bayer Healthcare and Genzyme; honoraria or consultation fees from BayerHealthcare, BiogenIdec, EMD Canada, Genzyme, Novartis, Sanofi-Aventis, Teva Canada Innovation; is part of the advisory boards/boards of directors for BayerHealthcare, BiogenIdec, Hoffman La-Roche, Merk Serono, Novartis, Opexa, Sanofi-Aventis; and has participated in a Genzyme sponsored speaker’s bureau. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation
Arianna Sartori†1 MD, Dawn Carle2 RN BScN & Mark S Freedman3 MSc MD FANA FAAN FRCPC † Author for correspondence 1 University of Trieste, Ospedale di Cattinara - Azienda Ospedaliero-Universitaria Ospedali Riuniti, Department of Medical, Surgical and Health Sciences (Neurology), 447 Strada di Fiume, 34149 Trieste, Italy Tel: +39 040 399 4321; Fax: +39 040 910 861; E-mail: [email protected] 2 Coordinator Clinical Research, University of Ottawa, Department of Medicine (Neurology), 501 Smyth Road, Ottawa, ON K1H 8L6, Canada 3 Professor of Medicine (Neurology), University of Ottawa, Department of Medicine (Neurology), 501 Smyth Road, Ottawa, ON K1H 8L6, Canada
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Teriflunomide: a novel oral treatment for relapsing multiple sclerosis 1.
Introduction
2.
Pharmacodynamics
3.
Pharmacokinetics and
Arianna Sartori†, Dawn Carle & Mark S Freedman †
University of Trieste, Ospedale di Cattinara - Azienda Ospedaliero-Universitaria Ospedali Riuniti, Department of Medical, Surgical and Health Sciences (Neurology), Trieste, Italy
metabolism 4.
Clinical trials
5.
Safety and tolerability
6.
Regulatory affairs
7.
Conclusion
8.
Expert opinion
Introduction: Multiple sclerosis is a disabling chronic inflammatory disease of the CNS. New emerging oral treatments can offer efficacy with higher levels of therapeutic adherence. Teriflunomide is one such oral agent that has recently been approved for the treatment of relapsing multiple sclerosis (RMS). Areas covered: The aim of this review is to describe the pharmacological profile of teriflunomide and review the vast clinical development program that paved the way for its approval, with emphasis on its safety and tolerability. Expert opinion: Teriflunomide is a safe new oral medication for treating RMS. It is effective at reducing relapses, MRI activity and slowing disability progression. It is well tolerated, with mild and transitory side effects. Although teriflunomide is given a pregnancy category ‘X’ by the FDA and an effective contraception is needed, to date, there has been no evidence of teratogenicity in humans and a rapid washout procedure can lead to a virtually complete elimination. Its effectiveness appeared to be at least comparable to that of high-dose IFN-b-1a, and although direct comparisons with other orals are still lacking, its tolerability and encouraging safety data suggest that teriflunomide could be considered an ideal first-line medication for RMS. Keywords: disease-modifying therapy, oral agent, relapsing multiple sclerosis, teriflunomide Expert Opin. Pharmacother. (2014) 15(7):1019-1027
1.
Introduction
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS that causes demyelination and axonal loss; it represents one of the most important causes of disability in young adults. Only 20% of patients experience a progressive form at onset (primary progressive MS), whereas the majority of patients present with a relapsing-remitting course that can eventually turn into secondary progressive disease [1]. Several medications are currently available to reduce the number of relapses, reduce MRI activity and delay progression of disease, but few have ever been definitively shown to prevent the transition to the secondary progressive phase. Moreover, they are often associated with side effects that can reduce tolerability. Overview of the market The first available disease-modifying drugs (DMD) for relapsing MS (RMS) were injectable and included IFN-b-1a, IFN-b-1b and glatiramer acetate (GA). Despite an excellent long-term safety profile, injection site reactions, flu-like syndromes and the injection itself still represent an obstacle to the achievement of the highest levels of adherence. Oral therapies could therefore fulfill the unmet need for a more tolerable therapy, leading to improved adherence and, as a result, effectiveness. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator [2], was the first oral drug to receive North American and European regulatory approval, but there 1.1
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Teriflunomide Currently III -- IV RMS DHODH inhibitor and subsequent inhibition of de novo pyrimidine synthesis Route of administration Oral Chemical structure C12H9F3N2O2 Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/19/14 For personal use only.
Drug name Phase Indication Pharmacology
CH3
N
2. OH
O
NH
F
F F
Pivotal trial(s)
TEMSO, TOWER, TENERE, TOPIC
DHODH: Dihydroorotate dehydrogenase; RMS: Relapsing multiple sclerosis.
is still some hesitation in the regular use of this drug, related at least partially to a concern regarding cardiovascular adverse events. Promising next-generation selective sphingosine receptor modulators, such as siponimod [3], ponesimod [4] and ceralifimod [5], are currently under study, with the hope of providing similar efficacy but with a better safety profile. Dimethyl fumarate (DMF), a fumaric acid ester, has been recently approved in many countries, including Canada and the USA as a treatment for RMS [6]. This agent is the main component of a combination of fumaric acid esters (Fumaderm) used in Germany for the treatment of psoriasis. The mechanism of action is not completely understood: it exerts a positive anti-inflammatory effect by mainly acting upon a transcription factor (the nuclear factor erythroid 2-related factor 2 (Nrf-2)). The medication ultimately can be well tolerated despite early side effects of flushing and gastrointestinal (GI) disturbances (diarrhea, nausea, abdominal pain), which diminish after the first months. A recent report of some cases of progressive multifocal leukoencephalopathy (PML) in patients with psoriasis treated with Fumaderm is raising some safety concerns with DMF treatment in MS [7,8]. Laquinimod is another oral drug with an unknown mechanism of action, which showed some early promise in clinical trials in that despite a relatively modest effect on relapse and MRI activity reduction, it appeared to have a statistically significant effect at slowing expanded disability status scale (EDSS) progression, as well as reducing brain atrophy compared with placebo [9]. 1020
Introduction to the compound and chemistry Teriflunomide is a once-daily oral medication approved in many countries for the treatment of RMS (Box 1). It is the most important active metabolite of leflunomide, a synthetic low-molecular-weight isoxazole derivative, previously used for the treatment of active rheumatoid arthritis for the past 15 years. 1.2
Box 1. Drug summary.
Pharmacodynamics
Teriflunomide acts as a noncompetitive and reversible inhibitor of the dihydroorotate dehydrogenase (DHODH), the fourth mitochondrial enzyme of de novo pyrimidine synthesis [10]. As a consequence, it inhibits the proliferation of highly dividing cell pools and in particular, T- and B-activated autoreactive cells, thought to be responsible for the inflammation and damage observed in MS. The pyrimidine salvage pathway is spared, and this allows maintenance of a protective immunity despite treatment. Teriflunomide is effectively a cytostatic drug, not cytotoxic, as it does not affect lymphocyte viability. In an in vitro study on stimulated peripheral blood mononuclear cells (PBMCs), teriflunomide showed a significant dose-dependent and reversible inhibition of T- and B-cell proliferation but only a little to no impact on their activation [11]. Further evidence supporting this observation comes from the pooled analysis of the safety data from three placebo-controlled teriflunomide studies (involving > 2500 patient-years of teriflunomide exposure) showing that the maximum mean decreases in neutrophil and lymphocyte counts were ~ 15%, but the mean absolute counts were within normal range and there was no association with increased number of infections [12]. Teriflunomide-treated patients maintain their ability to mount effective immune responses to seasonal influenza vaccination [13]; they also mount lower but effective antibody response and substantially equal cellular responses to Rabies vaccine as compared with placebo [14]. Finally, it has been very elegantly demonstrated in vitro that the suppressive effect of teriflunomide on T cells might depend on the quality of T-cell activation: it does not act as a nonselective suppressor of T-cell proliferation and expansion, but it blocks only the high-affinity T-cell clones’ expansion, although the low affinity T-cell clones are free to exert the immune response. In particular, it exerts a strong action only upon high-affinity T-cell receptor (TCR) stimulation and with high antigen concentrations although the effects upon low affinity TCR are modest. This translates into a selective immune modulation rather than a nonselective suppression of T-cell proliferation/ expansion as previously thought [15]. Many other DHODH-independent functions of teriflunomide have been invoked, but their relevance in vivo is still questioned. Indeed, in vitro models have shown its capacity to inhibit tyrosine kinases, MAPKs, nuclear factor k-lightchain-enhancer of activated B cells and cyclooxygenase-2;
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Teriflunomide
however, the concentrations used in these models are at least an order of magnitude higher than the concentrations needed to exert its effect on DHODH [16]. Teriflunomide also prevented stimulated PBMCs to express or release proinflammatory cytokines such as IL-6, IL-8 and monocyte chemotactic protein-1 with a DHODH-independent mechanism [11]. Teriflunomide was also shown to be efficacious in a number of animal models. In the Dark Agouti (DA) rat model of experimental autoimmune encephalomyelitis (EAE), which can more closely mimic the relapsing remitting course MS, teriflunomide reduced inflammation, axonal damage and functional deficits both in a prophylactic and therapeutic setting, and in a dose-dependent manner [17]. Moreover, teriflunomide prevented the EAE-increased latencies in somatosensory-evoked potentials and, as more recently demonstrated, in motor-evoked potentials [18]. Teriflunomide treatment attenuated the number of spinal cord-infiltrating T cells, natural killer cells, macrophages and neutrophils in DA rats with EAE, and it tended to normalize peripheral immune cell changes induced by the disease [19]. Teriflunomide has also been shown to decrease CSF levels of the chemokines CXCL9 and CXCL10 in Theiler’s encephalomyelitis virus-induced demyelinating disease model of MS, induced in SJL mice [20]. 3.
Pharmacokinetics and metabolism
The median half-life (t1/2) of the compound is 18 -- 19 days after repeated oral doses of 7 and 14 mg and it takes 3 months to reach the steady-state concentrations. It is > 99% plasma protein bound, therefore it has an approximately 100% bioavailability and a distribution volume of 11 l [21]. Teriflunomide metabolism is hepatic and requires hydrolysis, oxidation, N-acetylation and sulfate conjugation, with minimal burden for cytochrome P450. The unchanged drug undergoes direct biliary excretion, while the kidney excretes the majority of its metabolites. The enterohepatic recycling process allows teriflunomide to be reabsorbed in the small intestine and to be carried again in the liver through the portal circulation [22]. Therefore, it has very slow plasma elimination and it takes from 8 to 24 months to reach levels below 0.02 µg/ml. Nevertheless, if needed (e.g., unexpected serious adverse event (SAE) or pregnancy), it can be easily eliminated with an accelerated procedure that forms insoluble complexes bound in the small intestine, leading to a > 98% of decrease in plasma teriflunomide concentrations. For this purpose, either cholestyramine (8 g three times daily for 11 days) or activated charcoal (50 g activated charcoal twice daily for 11 days) can be used [23]. 4.
Clinical trials
Phase II studies The Phase II study [ClinicalTrials.gov identifier: NCT01487096] [24] aimed to examine the safety, efficacy 4.1
and optimal oral administration dose of the drug in patients with RMS. It was a randomized, double-blind, placebocontrolled, parallel-group trial with an MRI metric primary end point (number of combined unique [CU] active lesions). The study involved 179 patients who were randomized (1:1:1) and treated with placebo (n = 61), teriflunomide 7 mg/day (n = 61), or teriflunomide 14 mg/day (n = 57) for 36 weeks. There was a significant reduction in the median CU number in both treatment groups (teriflunomide 7 mg = 0.2, p < 0.03; teriflunomide 14 mg = 0.3, p < 0.01) compared with placebo (0.5), as well as a lower number of gadolinium (Gd)-enhanced lesions and of new or enlarging T2 lesions. There was a trend towards the reduction of the annualized relapse rates (ARRs) versus placebo-treated patients (mean ± SD = 0.58 ± 0.85 and 0.55 ± 1.12 vs 0.81 ± 1.22; p = NS). Despite these modest relapse results, it was of interest that teriflunomide 14 mg/day group showed a lower increase of disability (EDSS score) compared with the placebo group (7.4 vs 21.3%; p = 0.04). 4.2
Phase III studies TEMSO
4.2.1
The TEriflunomide Multiple Sclerosis Oral trial (TEMSO; ClinicalTrials.gov identifier: NCT00134563) was the first teriflunomide Phase III study; a double-blind, placebocontrolled study that enrolled 1088 patients with RMS, randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg, or 14 mg of teriflunomide once daily for 108 weeks [25]. Inclusion criteria were 18 -- 55 years of age, RMS according to the McDonald criteria [26] (with or without progression), an EDSS score £ 5.5, ‡ 2 clinical relapses in the previous 2 years (or one in the previous), and no attacks in the 60 days before randomization. The demographic and clinical characteristics at baseline were well balanced between three groups. The primary end point was met as teriflunomide significantly reduced the adjusted ARRs (95% CI) (0.54 for placebo vs 0.37 for teriflunomide at either 7 or 14 mg; p < 0.001 for both comparisons), as well as the secondary end point, consisting of the reduction in sustained disability progression, although no significant result was observed in the 7 mg group. Also, MRI end points were met: significantly lower total lesion volume (key MRI endpoint), fewer Gd-enhancing lesions and unique active lesions were observed in both teriflunomide groups compared with placebo [27]. Changes on brain atrophy and effect on fatigue did not differ significantly among the three groups. A prespecified subgroup analysis showed a constant and significant superiority of both treatment groups across all subgroups (stratification according to age, gender, geographical region, clinical disease characteristics, relapses in the past 2 years, MS subtype, MRI basal features, previous use of DMDs) [28]. Also, sustained disease-free activity was considered in the post hoc analysis, underlying a significant advantage for both treatment groups compared with placebo (disease-free patients were 14.3% in the placebo group, 18.4% in the 7 mg teriflunomide group and 22.9% in
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the 14 mg teriflunomide group [p = 0.0293 and p = 0.0002 vs placebo, respectively]) [29]. Finally, both teriflunomide 7 and 14 mg treatment reduced the annualized rates of relapses with sequelae, the relapses leading to hospitalization or requiring i.v. corticosteroids, and teriflunomide 14 mg also decreased annualized rates of all hospitalizations [30]. In the TEMSO extension study (ClinicalTrials.gov identifier: NCT00803049), patients who previously received placebo were re-randomized 1:1 to teriflunomide 7 or 14 mg. The 8-year follow-up (cutoff June 2012) confirmed low relapse rates, with an unchanged safety profile [31]. TOWER The second Phase III clinical trial (Teriflunomide Oral in People with Relapsing-Remitting Multiple Sclerosis [TOWER]; ClinicalTrials.gov identifier: NCT00751881) enrolled 1096 patients with the same inclusion criteria; the duration of the study was variable according to the timing of enrollment as it ended when the last patient included completed 48 weeks of treatment. The results confirmed what TEMSO study already stated: there was a significant reduction of the annual relapse rate (ARR) in both teriflunomide groups compared with placebo (teriflunomide 7 mg reduced ARR by 22.3%; p = 0.018; teriflunomide 14 mg reduced 36.3%; p < 0.001). The effect on the disability progression was significant only for the highest dosage (31.5%, p = 0.044) [32]. Similarly, in the TOWER post hoc analyses, it was clear that teriflunomide significantly reduced the number of relapses with sequelae and need of corticosteroid treatment [33]. Overall, ARR was reduced by 33.7 and 27% with teriflunomide 14 and 7 mg, respectively (p < 0.0001 vs placebo in both dosages). Disability progression was reduced by 30.5% (p = 0.0029) with only the higher 14 mg dosage, while teriflunomide 7 mg effect did not reach the statistical significance, as shown in the pooled efficacy data from TEMSO and TOWER [34]. Similarly, teriflunomide reduced also relapses with sequelae, relapses leading to hospitalization, those requiring corticosteroids, and teriflunomide 14 mg also reduced severe relapses (defined by Panitch) [35,36].
or IFN-b-1a on the primary composite end point (time to failure, defined as the first occurrence of confirmed relapse or permanent treatment discontinuation for any cause). Although teriflunomide was not found to be superior, it appeared to have an effect on ARR that was not significantly different than IFN-b-1a (IFN-b-1a = 0.22 vs teriflunomide 14 mg = 0.26, p = 0.6), whereas teriflunomide 7 mg showed paradoxically a significantly higher ARR compared with IFN-b-1a. The changes in the Fatigue Impact Scale favored teriflunomide as well as the mean scores in the Treatment Satisfaction Questionnaire for Medication (version 1.4), evaluating fatigue and treatment satisfaction, respectively [37].
4.2.2
TENERE TENERE (TErifluNomidE and REbif; ClinicalTrials.gov identifier: NCT00883337) was the first Phase III, raterblinded study, in which teriflunomide was compared with IFN-b-1a to evaluate its effectiveness, safety and tolerability in patients with RMS. The inclusion criteria remained the same as the other studies, but patients with history of prior use of subcutaneous IFN-b-1a, teriflunomide, leflunomide, prior or ongoing use of natalizumab, cladribine, mitoxantrone, or other immunosuppressants, or use of other IFNs, GA, intravenous immunoglobulins, or cytokine therapy within 3 months were excluded. A total of 324 patients were randomized 1:1:1 to teriflunomide 7 or 14 mg (double-blind) or subcutaneous IFN-b-1a 44 mcg t.i.w. (open-label). The study failed to show any difference between either dose of teriflunomide 4.2.3
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TOPIC The effectiveness of teriflunomide in patients with clinically isolated syndrome (CIS) was assessed in the TOPIC study (ClinicalTrials.gov identifier: NCT00622700), a doubleblind, placebo-controlled, parallel-group study. A total of 618 CIS patients were randomized to placebo, teriflunomide 7 or 14 mg. The slow recruitment due to the availability of other medications for CIS treatment together with the introduction of the newer 2010 diagnostic criteria [38], which rendered obsolete the primary end point, led to the premature interruption of this study. Collected data have been evaluated and both the primary and the key secondary end points were met: there was a reduction of the risk to convert to clinically definite MS (CDMS) by 42.6% (p = 0.0087) and 37.2% (p = 0.0271) in the 14 and 7 mg groups, respectively, compared with placebo. Moreover, a significant reduction of the risk of occurrence of new relapse or new MRI lesion was observed in both active treatment groups [39]. 4.2.4
Adjunctive therapy studies Teriflunomide has been purposed also in association with other immunomodulatory therapies with different mechanisms of action. It was administrated as adjunctive treatment to ongoing GA for 6 months, with a 6-month extension (ClinicalTrials.gov identifier: NCT00489489) [40]. A total of 123 RMS patients were randomized (1:1:1) to placebo, teriflunomide 7 mg and teriflunomide 14 mg, and the association with 7 mg teriflunomide demonstrated a significant reduction in the number of T1-Gd lesions and relative risk reductions of 64% (p = 0.031) and 47% (p = 0.193) with 7 and 14 mg, respectively. These results probably reflected the higher baseline MRI disease activity in the 7 mg group. Another Phase II trial randomized 118 patients on stable dose of IFN-b therapy to placebo, teriflunomide 7 mg, or teriflunomide 14 mg adjunctive therapy (1:1:1) [41], and the respective adjusted ARRs were 0.343, 0.231 and 0.144 (relative decrease in ARR of 32.6% [p = 0.4355] and 57.9% [p = 0.1005] in 7 and 14 mg groups, respectively, vs placebo). A significantly unexpected reduction in the number of T1-Gd lesions in both teriflunomide dosage groups was observed, which was greater than was seen with either IFN-b or teriflunomide alone, suggesting an additive or synergistic effect of the combination. 4.3
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These encouraging results led to TERACLES, a Phase III study (ClinicalTrials.gov identifier: NCT01252355) testing the efficacy and tolerability of teriflunomide in combination with IFN-b [42]. The study has been prematurely interrupted, and the data analysis is ongoing. 5.
Safety and tolerability
5.1
Overview of TEAEs and SAEs
between the groups in the incidence of ALT > 3 upper limit of normal (ULN) and serious hepatic disorders [12]. None of the ALT elevations were associated with concomitant elevations in bilirubin. All the trial protocols required treatment discontinuation should ALT > 3 ULN occur on two consecutive laboratory measurements. Infections The occurrence of serious infections was rare (£ 2.5%) and similar in all groups, with an approximately 15% maximum mean decreases in neutrophil and lymphocyte counts (mean absolute counts within the normal range, no increased infection rate) [12].
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5.1.2
The safety profile was recently updated, pooling the data from the three double-blind studies, and both doses seemed to have a similar and manageable safety profile [12]. The analysis from 2430 patients (cumulative treatment exposure > 1225 patientyears per group) revealed that the treatment-emergent adverse events (TEAEs) more frequently reported were hair thinning, diarrhea, alanine aminotransferase (ALT) elevation, nausea and headache. Treatment discontinuations in the teriflunomide group were due to TEAEs (placebo 6.9%; teriflunomide 7 mg 11.0%; teriflunomide 14 mg 13.6%), but many of these were related to protocol requirements (repeated ALT elevations). The extension studies, with up to 9 years’ exposure to teriflunomide, showed no unexpected TEAEs. In particular, in the Phase II extension trial (ClinicalTrials. gov identifier: NCT00228163) [43], involving 147 patients from the core study, there were 15 (18.5%) and 13 (19.7%) patients in the 7 and 14 mg groups, respectively, who discontinued because of the occurrence of TEAEs. SAEs were reported in 29 (35.8%) and 19 (28.8%) patients in the 7 and 14 mg groups, respectively. They were increased hepatic enzymes (n = 10), increased ALT (n = 3), loss of consciousness (n = 3), pneumonia (n = 2), neutropenia (n = 2), breast cancer (n = 2) and MS relapse (n = 2). SAEs that led to discontinuation were described in 11 (13.6%) and 9 (13.6%) patients. The TEMSO extension trial [31] included patients treated for up to 8 years (cutoff June 2012). The most common TEAEs, whose incidence did not change between groups or increased with treatment duration, were nasopharyngitis, diarrhea, hair thinning, increased ALT, influenza, pain in extremity and headache. SAEs occurred in 20% of patients: increased ALT (n = 14), intervertebral disc protrusion (n = 7), venous stenosis (n = 4), urinary tract infection (n = 4) and pneumonia (n = 3). Overall, seven deaths occurred and none of them have been considered related to the treatment. One and three deaths were seen during the Phase II and the TEMSO study extensions, respectively, and three during the TOWER study (due to motor vehicle accident, suicide, sepsis) [32]. The TENERE study reaffirmed the same safety profile, with a lower discontinuation rate due to AEs in the teriflunomide group compared with the IFN-b-1a group [37]. The number of serious TEAEs and TEAEs leading to treatment discontinuation was low also in the adjunctive therapy studies [40,41]. Hepatic effects Teriflunomide treatment most often caused asymptomatic and transient ALT elevations, but there was no difference 5.1.1
Malignancies In the three placebo-controlled studies, neoplasms (benign or malignant) were very rarely observed (< 0.5% of patients; placebo n = 4; teriflunomide 7 mg n = 1; teriflunomide 14 mg n = 3), without a specific pattern of occurrence. No hematooncological cancers were reported. These data were confirmed by the extension studies, in which the prevalence of malignancies reflected the rates observed in the general population. 5.1.3
Blood pressure At week 108, a slight elevation in diastolic and more marked in systolic blood pressure was observed in the teriflunomide group compared with placebo (systolic: placebo -0.7, teriflunomide 7 mg +3.0, teriflunomide 14 mg +2.7; diastolic: placebo -0.7, teriflunomide 7 mg +1.4, teriflunomide 14 mg +1.6) [12]. In spite of the slight blood pressure elevation in the teriflunomide group, none of the cases was severe or led to therapy discontinuation. 5.1.4
GI symptoms The most frequently reported TEAEs are diarrhea and nausea, which are usually of mild or moderate intensity, and their incidence is higher during the first 3 months of treatment, which then tends to decrease. They usually resolve spontaneously [44]. 5.1.5
Hair loss/hair thinning The analysis of the data from the Phase II and TEMSO studies showed that hair thinning/loss was more common in the teriflunomide group, with a trend towards a dose--effect (placebo 4.3%, teriflunomide 7 mg 11.4% and teriflunomide 14 mg 15.2%). Less than one per cent of patients discontinued treatment because of that TEAE and usually it was graded as mild (73%) or moderate in intensity. The type of hair thinning/loss was telogen effluvium, characterized by acceleration toward the resting phase of the follicular growth cycle. This is a reversible phenomenon, which in the majority of the patients resolved spontaneously within 3 -- 6 months, without sequelae (85%) and while patients were still on treatment [45]. 5.1.6
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5.1.7
Peripheral neuropathy
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In the TEMSO study, 10 confirmed cases of peripheral neuropathies were observed (1.2% of the teriflunomide 7 mg group and 1.9% of the teriflunomide 14 mg group); no cases in the placebo group were reported. In particular, there were five mononeuropathies related to carpal tunnel syndrome or nerve compression, and three resolved spontaneously during treatment [25]. Pregnancy The teratogenic potential of leflunomide, suggested by animal models, led to the required reliable contraception during clinical trials as well as during the postmarketing use. In spite of that, a total of 81 pregnancies were reported in female patients and 20 in partners of male patients (clinical trial database, data cutoff 9 April 2013). One study, with eight pregnancies, remains blinded. The available outcomes from 63 pregnancies in women exposed are as follows: 20 healthy newborns, 26 induced abortions, 12 spontaneous abortions and 5 ongoing pregnancies. Pregnancy outcomes from 16 in partners of men exposed to the drug are 12 healthy newborns, 1 induced abortion, 1 spontaneous abortion and 2 ongoing pregnancies. No structural defects or functional deficits were noticed in newborns. The 19% spontaneous abortion rate reflects the rates in similar MS patients [46]. Even though the safety data are encouraging, patients should use reliable contraception while on teriflunomide as well as discontinue treatment and undergo accelerated elimination (with cholestyramine or activated charcoal) prior to conceiving. Recently presented experimental data from in vitro and in vivo (animal model) studies showed that teriflunomide has no effects on sperm DNA [47]. 5.1.8
6.
Regulatory affairs
Teriflunomide has been approved for the treatment of RMS by the US FDA in September 2012 (7 and 14 mg dosages) and by the European Medicines Agency in August 2013 (only 14 mg dosage) and in November 2013 also in Canada and Australia. 7.
Conclusion
Teriflunomide is a recently approved oral DMD for RMS, with a once-daily dosing. Its properties affecting the pool of nucleotides used by rapidly dividing cells but not changing cell DNA structure ultimately leading to fewer autoimmune T cell make it more like an immunomodulator rather than an immunosuppressant. Phase II and III studies showed reduction in ARRs, MRI activity and disability progression in treated patients. In the head-to-head study, teriflunomide was not superior to IFN-b-1a, but produced relapse rate reductions not significantly different from the high-dose IFN-b-1a, although comparisons with other DMDs are still lacking. In the CIS population, it reduced the risk to convert 1024
to CDMS. It has an excellent safety profile, confirmed also in the adjunctive therapy studies. 8.
Expert opinion
Teriflunomide most clearly showed its effects on the primary outcome measure of ARR reduction, though the 14 mg dose also repeatedly showed significant slowing of EDSS progression and a reduction in most important secondary MRI end points -- findings that were consistent across the different patient subgroups analyzed in both TEMSO and TOWER trials [28,32]. It did not have a significant effect on slowing brain atrophy relative to placebo over 2 years in TEMSO. Nevertheless, it is a simple, safe and well-tolerated oncedaily oral treatment, which is thus seen as an advantage over any of the current self-injectable therapies. Its main disadvantage over the injectables is the lack of long-term nontrial safety data. The injectables have proven to be extremely safe as they have been used for almost 30 years without significant concerns, but teriflunomide has a 12-year history of extremely encouraging clinical trial data to add to a much longer history of its parent drug leflunomide in the treatment of rheumatoid arthritis. Teriflunomide produced thus far no unexpected severe adverse events or deaths in any study. It was very well tolerated, and the main side effects reported were mild and transitory. In particular, GI side effects usually resolved in the first 3 months and they led to discontinuation of study therapy in only a small percentage of patients (teriflunomide 7 mg = 1.4%, teriflunomide 14 mg = 1.1%, placebo = 0.3%) [44]. Also, hair loss/thinning was transitory and usually resolved spontaneously while still on treatment without sequelae, which distinguishes this type of hair loss from that seen frequently with the use of chemotherapy. As with GI side effects, discontinuations due to hair loss occurred only in a very few cases (teriflunomide 7 mg = 0.5%, teriflunomide 14 mg = 1.4%, placebo = 0%) [45]. Finally, one of the main concerns is the potential teratogenic action of teriflunomide, which was based on the noted effect of its parent drug leflunomide in animal models leading to the FDA ‘X’ rating for safety in pregnancy. Regardless, pregnancies did occur during the clinical trial program of teriflunomide and an ongoing registry continues to collect postmarketing information, and thus far there is no clear evidence of teratogenicity in humans [46]. By no means does this suggest it is safe to take during pregnancy and effective contraception remains fundamental as it does for the other available MS treatments. Some feel that this potential for teratogenicity, however not realized in > 15 years of combined monitoring of leflunomide [48,49] and teriflunomide, warrants it being relatively contraindicated for young fertile women. However, we take the opposite view as teriflunomide is the only diseasemodifying medication for which there is a highly effective and simple procedure for its complete elimination from the body that takes < 2 weeks. Thus, a young woman wishing to become pregnant needs only to perform the ‘washout’
Expert Opin. Pharmacother. (2014) 15(7)
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Teriflunomide
procedure using cholestyramine or charcoal, then gets a free serum teriflunomide blood test showing levels of teriflunomide below that of teratogenic potential, and she would be safe to conceive immediately. The safety of all other therapies is not established, but neither is the time it takes to wash out the other treatments from the body. Most physicians arbitrarily recommend waiting 2 -- 3 months following the cessation of an MS treatment before trying to conceive. Direct comparisons to other oral therapies are still lacking. In the CONFIRM [50] study, although not statistically powered for a comparison between DMF and GA, the drugs did not appear to differ in terms of ARR reduction. In the TRANSFORMS study [51], Fingolimod demonstrated its superiority to low-dose once-weekly IFN-b-1a IM in reducing ARR and MRI activity. Although we do know that teriflunomide effectiveness is at least comparable to high-dose IFN-b-1a, which has been shown to be more efficacious than once-weekly IFN-b-1a IM [36,52], in the TENERE study it was not more effective than high-dose IFN-b-1a SC in terms of relapse reduction or treatment discontinuations. Once physicians realize the simplicity and safety of teriflunomide, it should be readily embraced as a first-line alternative therapy to the injectables. Its tolerance profile and once-daily regimen are advantages over DMF, offering somewhat comparable efficacy in most countries for a cheaper price. Moreover, recently the Canadian Drug Expert Committee recommended, based on a cost-effectiveness analysis, that DMF should be used for the treatment of RRMS only Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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if the patient has failed to respond to adequate courses of at least one IFN-b formulation and GA [53]. Until properly conducted comparator trials are performed, which are unlikely, it will be difficult to know how any of the oral agents do relative to each other let alone the incumbent therapies. Longer-term ‘real-world’ safety data might well indicate which agent may be more risky; already there are concerns that DMF, at least in the treatment of psoriasis, might be a risk for the development of PML [7,8]. We envisage teriflunomide to take a foothold of first-line therapies for MS around the world, having the most extensively studied oral agent in CIS and in three Phase III trials in RMS and now planning to be studied in the pediatric population.
Declaration of interest MS Freedman has received research grants from Bayer Healthcare and Genzyme; honoraria or consultation fees from BayerHealthcare, BiogenIdec, EMD Canada, Genzyme, Novartis, Sanofi-Aventis, Teva Canada Innovation; is part of the advisory boards/boards of directors for BayerHealthcare, BiogenIdec, Hoffman La-Roche, Merk Serono, Novartis, Opexa, Sanofi-Aventis; and has participated in a Genzyme sponsored speaker’s bureau. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation
Arianna Sartori†1 MD, Dawn Carle2 RN BScN & Mark S Freedman3 MSc MD FANA FAAN FRCPC † Author for correspondence 1 University of Trieste, Ospedale di Cattinara - Azienda Ospedaliero-Universitaria Ospedali Riuniti, Department of Medical, Surgical and Health Sciences (Neurology), 447 Strada di Fiume, 34149 Trieste, Italy Tel: +39 040 399 4321; Fax: +39 040 910 861; E-mail: [email protected] 2 Coordinator Clinical Research, University of Ottawa, Department of Medicine (Neurology), 501 Smyth Road, Ottawa, ON K1H 8L6, Canada 3 Professor of Medicine (Neurology), University of Ottawa, Department of Medicine (Neurology), 501 Smyth Road, Ottawa, ON K1H 8L6, Canada
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